The brain possesses remarkable plastic capabilities which adapt its circuitry in the course of normal function and in response to injury. We will continue studies on synaptic plasticity and remodeling focusing on the hippocampus as a model system. Recently, we reported that brain transplants survive better if placed in an injury several days after it is sustained. This correlated with an increase in neurotrophic factors. In our initial studies we used peripheral cultured neurons as an assay system. Now we will extend these studies using centrally derived neurons and characterize the nature of the factors. We will also determine whether or not injury produced by ischemia causes an increase in neurotrophic factors. These results together with previous results from mechanical and cytotoxic lesions should allow us to determine whether the response of neurotrophic factors to injury is general to several types of injury. Results from in vitro cell culture will be used to optimize the survival and growth of transplants and to explore the possibility that even adult neurons can be transplanted. Many of our transplant studies will focus on replacing the entorhinal cortex. In transplant studies carried out in the previous grant period we studied septal, striatal and raphe transplants. We found that raphe transplants do not form synapses. In order to complete this series of studies we plan to study whether cholinergic transplants form synapses using a monoclonal antibody to choline acetyltransferase. There is extensive information on the consequences of removal of the entorhinal cortex and now we will study its capacity to restore the circuitry to normal. The inputs and outputs of the transplants will be studied and we will determine how the outputs interact with lesion induced sprouting. In this series of studies we will also analyze the distribution of acidic amino acid receptors after lesions and after transplants using a newly developed autoradiographic technique. Overall we plan to study the requirements of neural survival and growth in vivo and in vitro and using conditions for optimal transplantation of neurons, rigorously analyze the circuits formed and the junctions restored.